The conventional methods of manufacturing 2',3'-dideoxy-.beta.-nucleoside include, for example,
a method in which the hydroxyl groups in the 2'-and 3'-positions are selectively removed from (i) ribonucleoside derivatives or (ii) 2'-deoxynucleoside derivatives, and PA1 (iii) a method utilizing a condensation reaction between a 2,3-dideoxyribose derivative and a base which is a composition of a nucleoside. PA1 (a) preparing a 2,3-dideoxy-2,2-di(organothio)pentofuranose derivative (IV) from a 5-hydroxypentane-4-olide derivative (VI); PA1 (b) carrying out a condensation reaction between the prepared 2,3-dideoxy-2,2-di(organothio)pentofuranose derivative (IV) and a 5-substituted pyrimidine derivative (V) to prepare a 1-[2,3-dideoxy-2,2-di(organothio)-.beta.-D-pentofuranosyl]pyrimidine derivative (III); PA1 (c) desulfurizing and reducing the 1-[2,3-dideoxy-2,2-di(organothio)-.beta.-D-pentofuranosyl]pyrimidine derivative (III) prepared in step (b) to prepare a 1-(2,3-dideoxy-.beta.-D-pentofuranosyl)pyrimidine derivative (II); and PA1 (d) subjecting the 1-(2,3-dideoxy-.beta.-D-pentofuranosyl)pyrimidine derivative (II) prepared in step (c) to a reaction for removing the protective group so as to obtain 2',3'-dideoxy-.beta.-nucleoside derivative (I): ##STR2## where R.sup.1 to R.sup.5, X, Y and Z are represented as follows: R.sup.1 to R.sup.3, which may be the same or different, are alkyl or phenyl group, which may be substituted; PA1 R.sup.4 is a protective group of a hydroxyl group; PA1 R.sup.5 is alkyl or phenyl group, which may be substituted; PA1 X is oxygen or nitrogen atom, said nitrogen atom having another atom or an atomic group; PA1 Y is hydrogen atom, halogen atom, alkyl group or alkenyl group, said alkyl or alkenyl group being possibly substituted with a halogen atom; and PA1 Z is halogen atom, acyloxy, alkyloxy or aryloxy group, said alkyloxy and phenyloxy groups being possibly substituted.
An example of conventional method (i) is described in, for example, "J. Org. Chem., 1988, vol. 53, page 5170". It is described that 2',3'-cyclic ortho ester of uridine is thermally decomposed to obtain 2',3',-dideoxy-.beta.-uridine. Then, the base of the nuclooside thus obtained is replaced by another base by using a special strain of Escherichia coli.
An example of conventional method (ii) is described in, for example, "Synth. Commun., 1985, vol. 15, page 401". It is described that the hydroxyl group in the 3'-position of 2'-deoxynucleoside is converted into a thiocarbonate ester, followed by subjecting the resultant compound to a deoxidation reaction.
Further, conventional method (iii) is exemplified in, for example, Japanese Patent Application No. 2-6970 filed by the present inventors, "Heterocycles, 1990, vol. 31, page 2041", "Tetrahedron Lett., 1988, vol. 29, page 1239, Falina et al" and "J. Org. Chem., 1988, vol. 53, page 4780, Okabe et al".
In conventional method (i), however, it is necessary to use a bacterium which is difficult to obtain in general. Also, in each of conventional methods (i) and (ii), ribonucleoside derivatives available in the nature are used as raw materials. Thus, in the case of manufacturing various derivatives, it is necessary to prepare a synthetic riboculeoside, followed by converting the synthetic riboculeoside into the desired 2',3'-dideoxy-.beta.-nucleoside derivative.
On the other hand, the conventional method (iii) is poor in its stereoselectivity. Specifically, the product obtained by the conventional method (iii) is a mixture of a desired .beta.-isomer and a .alpha.-isomer as byproduct. The mixing ratio of .beta.:.alpha. is 7:3 even in the highest case. In general, the .beta.- and .alpha.-isomers are mixed in the equivalent amount.
A measure for solving the above-noted problems inherent in the conventional methods is proposed in, for example, Japanese Patent Application No. 2-133913 and "Chem. Lett., 1990, page 1549". It is proposed that a condensation reaction is carried out between a 2,3-dideoxy-2-.alpha.-(organothio)pentofuranose derivative and a 5-substituted pyrimidine derivative in the presence of Lewis acid so as to obtain a 1-(2,3-dideoxy-2-organothio-.beta.-D-pentofuranosyl) pyrimidine derivative. The derivative thus obtained is oxidized in the presence of a peroxide to obtain 2',3'-dideoxy-2',3'-didehydro-.beta.-ribonucleoside via a 1-(2,3-dideoxy-2-organosulfynyl-.beta.-D-pentofuranosyl) pyrimidine derivative.
It should be noted that an organothio group is .alpha.-coordinated with the carbon atom in 2-position of the 2,3-dideoxy-2-.alpha.-(organothio)pentofuranose derivative used as one of the starting materials in the method described above. Thus, in the condensation reaction between the pentofuranose derivative and the 5-substituted pyrimidine derivative, the approach of the 5-substituted pyrimidine derivative toward the organothio group in an .alpha. direction is inhibited by the steric effect of the organothio group and involvement of the adjacent group. As a result, a high selectivity of the .beta.-isomer of the resultant pyrimidine derivative can be achieved. It follows that the method described above permits obtaining 2',3'-dideoxy-2',3'-didehydro-.beta.-ribonucleoside in a high stereoselectivity.
As described above, the conventional method described above permits achieving a high selectivity of the .beta.-isomer in the condensation reaction between the 2,3-dideoxy-2-.alpha.-(organothio)pentofuranose derivative and the 5-substituted pyrimidine derivative. However, it is difficult to obtain the .alpha.-isomer with a high stereoselectivity in the step of preparing the 2,3-dideoxy-2-.alpha.-(organothio)pentofuranose derivative, thus, the starting material, from a 5-hydroxypentan-4-olide derivative by the conventional method. As a result, the yield of the .beta.-isomer is relatively low, i.e., about 30%, in the process ranging between the step of obtaining 2,3-dideoxy-2-.alpha.-(organothio)pentofuranose derivative from the 5-hydroxypentan-4-olide derivative and the step of the condensation reaction.